The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. Forty-one patients with painful diabetic neuropathy completed a double-blind comparison of transdermal clonidine to placebo. Because previous work had suggested that only about one-quarter of these patients respond to clonidine, we used a novel two-stage study design in which responders in the initial clinical trial were entered into a second trial, aimed at confirming that they were consistent responders. In the overall group of 41 patients, the treatment difference between clonidine and placebo was not significant, but the 12 apparent responders from the first trial showed a 20% reduction in pain with clonidine, relative to placebo, during the second clinical trial. Brief sharp and shooting pains were more likely to respond to clonidine. The results support the hypothesis that there is a subset of patients with painful diabetic neuropathy who benefit from systemic clonidine and illustrate the value of an "enriched enrollment" clinical trial design in studying pain syndromes which may have diverse underlying mechanisms. Because of growing evidence from animal studies that neuropathic pain may be mediatd by spinal cord neurons activated via NMDA channels, the NMDA antagonist ketamine is being studied in two conditions: chronic pain in patients with nerve damage or reflex sympathetic dystrophy, and experimental pain in normal volunteers, consisting of hyperalgiesia of the skin briefly induced by intradermal injection of capsaicin. Ketamine reduced capsaicin-evoked pain and hyperalgesia in volunteers, and relieved pain and hyperalgesia in 6/8 patients with chronic neuropathic pain. Therapeutic effects only occurred at doses that also caused cognitive impairment, however.